Discosures Heterogeneity of Pulmonary Vascular The University - - PowerPoint PPT Presentation

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University Medical Center Groningen The Netherlands

11th International Conference Neonatal and Childhood Pulmonary Vascular Disease San Francisco 2018

Capturing the Clinical Heterogeneity of Pulmonary Vascular Disease in Children

R.M.F. Berger

University Medical Center Groningen The Netherlands

Discosures

• The University Medical Center Groningen contracts

with Actelion, Lilly and Pfizer for consultancy activities of RMF Berger

• No relevant disclosures related to this presentation

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Pulmonary Hypertension

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Congenital Heart Defects

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PH CHD

University Medical Center Groningen The Netherlands

Panama classification

• f pediatric pulmonary hypertensive vascular disease

Del Cerro et al. Pulm Circ 2011

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Clinical classification of PH: WSPH (Nice)

• 1. Pulmonary arterial hypertension

1.1 Idiopathic PAH 1.2 Heritable PAH

1.2.1 BMPR2 1.2.2 ALK1, ENG, SMAD9, CAV1, KCNK3 1.2.3 Unknown

1.3 Drug- and toxin-induced 1.4 Associated with:

1.4.1 Connective tissue disease 1.4.2 HIV infection 1.4.3 Portal hypertension 1.4.4 Congenital heart disease 1.4.5 Schistosomiasis 1’ Pulmonary veno-occlusive disease &/or pulmonary capillary haemangiomatosis 1’’ Persistent PH of the newborn (PPHN)

• 2. PH due to LHD

2.1 LV systolic dysfunction 2.2 LV diastolic dysfunction 2.3 Valvular disease 2.4 Congenital/acquired left heart inflow/outflow obstruction

• 3. PH due to lung diseases and/or hypoxia

3.1 COPD 3.2 Interstitial lung disease 3.3 mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental lung diseases

3.7.1 Congenital diaphragmatic hernia 3.7.2 Bronchopulmonary dysplasia

• 4. CTEPH
• 5. PH with unclear multifactorial mechanisms

5.1 Haematological disorders: chronic haemolytic anaemia, myeloproliferative disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: segmental PH, tumoural obstruction, fibrosing mediastinitis, chronic renal failure

Simonneau G, et al. J Am Coll Cardiol 2013; University Medical Center Groningen The Netherlands

Heterogeneity vs Classification

• Etiology
• Phenotype
• Co-morbidities
• Clinical course
• Genotype
• Pathophysiologic mechanisms
• Biomarkers
• Treatment response

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Classification… for who?

Subspecialists:

• NICU - Cardiology
• Pulmonary - PICU
• CICU - Others

Patients and Families Insurance Companies Practitioners and care providers Lab-Oriented Investigators Patient-Oriented Investigators Epidemiologists Regulatory

(FDA, EMA)

Pharmaceuticals

Slide courtesy of Steven Abman

University Medical Center Groningen The Netherlands

Characteristics of a Useful Classification System

• Simple yet useful
• Broad but not diffuse (e.g., “encyclopedic”)
• Internally consistent and easy to apply between providers and centers
• Provides a common language
• Enhance care and research approaches to improve:
• Early identification or anticipation of PH in at-risk subjects
• More rapidly obtain correct diagnosis
• Guide effective evaluation and therapies
• Recognize critical features,

common co-morbidities and disease modifiers

• Develop disease-specific strategies

Slide courtesy of Steven Abman

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Pediatric Pulmonary Hypertension

Epidemiology of Associated Conditions

A/1) van Loon RL et al Circulation 2011; 2) Berger RM et al. Lancet 2012; 3) Fraisse A et al. Arch Cardiovasc Dis 2010; 4) van Loon RL et al. J Pediatr 2009; 5) Barst RJ et al. Circulation 2012.

3265 pediatric PH patients

Pediatric Pulmonary Hypertension in the Netherlands, Period 1991-2005

University Medical Center Groningen The Netherlands

TOPP 1 Reveal-children 2 Reveal-Adults3 Patients, n 362 216 2525 Age at Dx (yrs), median 7.5 7 53 Female, % 59 64 80 Group 1: PAH 317 (88) 216 (100) 2525 (100) IPAH/HPAH 212 (53) 122 (56) 1166 (46) CHD 160 (40) 23 (36) 215 (10) CTD 9 (3) 10 (5) 639 (25) Portopulmonary 2 (1) 3 (1) 136 (5) Other 14 (4) 4 (2) 255 (10) Group 3: Lung disease 42 (12) NE NE Other 3 (1) NE NE

Epidemiology Pediatric PAH

data from large registries

• 1. Berger et al. Lancet 2012.

2. Barst et al. Circulation 2012. 3. Badesch et al. Chest 2010.

Values given are n (%) unless otherwise indicated

TOPP 1 Reveal-children 2 Patients, n 362 216 Age at Dx (yrs), median 7.5 7 Female, % 59 64 Group 1: PAH 317 (88) 216 (100) IPAH/HPAH 212 (53) 122 (56) CHD 160 (40) 23 (36) CTD 9 (3) 10 (5) Portopulmonary 2 (1) 3 (1) Other 14 (4) 4 (2) Group 3: Lung disease 42 (12) NE Other 3 (1) NE Center for Congenital Heart Disease

Beatrix Children’s Hospital UMC Groningen

Ploegstra et al Lancet Respir Med 2016

University Medical Center Groningen The Netherlands

Pediatric PAH

• Comorbidities 24% - 45%
• NL registry
• Spanish registry
• TOPP registry
• Multi-registry growth study
• Including
• Down syndrome

~10-15%

• Other genetic/syndromic abnormalities ~10-30%
• Non-genetic diseases

~10-20%

• Multiple “associated conditions”

~20-30%

van Loon et al, 2009 Cerro et al, 2011) Berger et al. Lancet 2012 Ploegstra et al Lancet Respir Med 2016

Relation to PAH

• Causal?
• Disease modifier?
• Bystander?

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Classification of Paediatric PH in Dutch National cohort: 1991-2005

Van Loon R, et al. Circulation. 2011

3263 PH

36 IPAH 111 PAH- CHD 3 PAH- CTD 1 PAH- HIV 3 PVOD/ PCH 1548 PPHN 1112 Flow-PAH 5 Without shunt 4 Pre-tricuspid shunt 40 Post-tricuspid shunt 7 Accelerated 38 APV 17 After shunt closure

2691 Transient PAH 154 Progressive PAH 2845 PAH 160 PH-left heart disease 5 CTEPH PH- multifactorial 253 PH-lung disease/hypoxia 61 Hypoventilation 192 Developmental lung disease 2691 Transient PAH 192 Developmental lung disease 154 Progressive PAH

34% 27%

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Slide courtesy of Steven Abman

University Medical Center Groningen The Netherlands

WHO group 3

Data from the TOPP registries

Parameter N

Enrolled patients 818 WHO group 3 80 BPD 36 Interstitial lung disease 15 Congenital pulmonary hypoplasia* 14 Chronic exposure to high altitude 12 Congenital diaphragmatic hernia 10 Sleep-disorder breathing/obstructive apnea 8 COPD 2 Kyphoscoliosis* 2 Other pulmonary disease with mixed restrictive and

• bstructive pattern**

1

20

Multiple answers allowed

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Grade of PVD Years 10 20 30 classic posttricuspid ES pretricuspid ?

Berger, Eur Heart J 2000 Galie, Eur Heart J 2016

PAH-CHD Evolution of pulmonary vascular disease

Center for Congenital Heart Disease

Beatrix Children’s Hospital UMC Groningen

Clinical Classification PAH-CHD (shunts) WSPH Nice 2014

• A. Eisenmenger syndrome

Includes all systemic-to-pulmonary shunts resulting from large defects and leading to a severe increase in PVR and a reversed (pulmonary-to-systemic) or bidirectional shunt; cyanosis, erythrocytosis, and multiple organ involvement are present

• B. PAH associated

with systemic-to-pulmonary shunts Includes moderate to large defects; PVR is mildly to moderately increased, systemic-to-pulmonary shunt is still prevalent, and no cyanosis is present at rest

• C. PAH with small defects

Small defects (usually ventricular septal defects <1 cm and atrial septal defects <2 cm of effective diameter assessed by echocardiography); clinical picture is very similar to idiopathic PAH

• D. PAH after corrective cardiac

surgery Congenital heart disease has been corrected, but PAH is still present immediately after surgery or recurs several months or years after surgery in the absence of significant postoperative residual lesions

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PAH-CHD

Ramjug et al. JHLT 2016 Moceri et al IJC 2014 Alonso-Gonzalez et al IJC 2015

Anatomic-Physiologic Classification

Haworth et al, Heart 2009

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Genotypes in Pediatric PAH

known PAH-genes

BMPR2 ACVRL1 ENG TBX4 Total Levy et al.

Eur Resp J 2016

5 14% 4 11% NT 3 8% 37 100% Harrison et al

Circulation 2005

2 13% 1 7% 1 7% NT 16 100% Kerstjens et al

J Med Genet 2013

3 15% NT NT 3 15% 20 100%

Rosenzweig et al JHLT 2008

8 10% NT NT NT 78 100%

Pfarr Respir Res 2013

4 14% 2 7% 1 (VUS) 4% NT 29 100%

Compared to adult PAH, the genetic architecture of pediatric PAH seems enriched in ACVRL1 and TBX4 mutations (Levy et al, 2016)

NT=Not Tested

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Comparison of Genetic Test Results in Adults and Children

Adult Pediatric (age < 18) FPAH IPAH

N=178 N=79 N=130 N=25

Slide Courtesy of Dr. Wendy Chung Circ Genom Precis Med. 2018 University Medical Center Groningen The Netherlands

TBX4 mutation variable phenotype and age of presentation

Older child with IPAH Neonate Acinar Dysplasia

Kerstjens et al J Med Genet 2013 Szafranski et al Am J Med Genet A. 2016

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Biomarkers in PAH Risk stratification

5th WSPH, Pediatric Task Force, JACC, 2013. Galiéet al., Eur Heart J, 2015.

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Pediatric Risk Stratification Model

Time (years) Transplant-free survival (%)

1 2 3 4 5 20 40 60 80 100 1 2 3 4 5

• No. of

low-risk criteria

p<0.001

Haarman et al, in preparation

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• 4. PH due to pulmonary artery obstruction
• 5. PH with unclear mechanisms
• 3. PH due to lung diseases and/or hypoxia
• 2. PH due to left heart disease
• 1. Pulmonary Arterial Hypertension

1.1 Idiopathic PAH 1.2 PAH with long-term response to Ca blockers 1.3 Heritable PAH (Table 1) 1.4 Drugs and Toxins induced (Table 2) 1.5 Associated with; 1.4.1 Connective tissue disease (Table 3) 1.5.2 HIV infection 1.5.3 Portal hypertension 1.5.4 Congenital heart diseases (Table 4) 1..5 Schistosomiasis 1.6 PAH with overt signs of venous/capillaries ( PVOD/PCH) involvement (Table 5 & 6) 1.7 PPHN Syndrome (Table P1) 2.1 PH due to Heart Failure with preserved E.F. 2.2 PH due to Heart Failure with reduced E.F. 2.3 Valvular Disease 2.4 Congenital Post-Capillary Obstruction (Table P2) 3.1 Chronic obstructive Lung Diseases 3.2 Interstitial Lung Diseases 3.3 Other LD with restrictive/obstructive pattern 3.4 Hypoxia without lung diseases 3.5 Developmental Lung Disorders (Table P3) 4.1 Chronic Thromboembolic PH 4.2 Other Pulmonary artery obstructions 5.1 Haematologic disorders (Table 8) 5.2 Systemic disorders ( Table 8) 5.3 Others 5.4 Complex CHD (Table P4)

clinical classification

(Neonatal) PH associated with developmental vascular lung disorders

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Developmental (vascular) Lung Disorders

associated with disturbed pulmonary vascular development

• Bronchopulmonary Dysplasia
• Congenital Diaphragmatic Hernia
• Down Syndrome
• Alveolar Capillary Dysplasia with “Misalignment of Veins” (FOXF1)
• Lung Hypoplasia, Acinar Dysplasia
• Surfactant Protein Abnormalities
• SPB deficiency / SPC deficiency / ABCA3
• TTF-1/Nkx2
• TBX4
• Pulmonary Interstitial Glycogenosis
• Pulmonary Alveolar Proteinosis
• Pulmonary Lymphangiectasia
• Scimitar syndrome
• Isolated unilateral absence of PA
• 4. PH due to pulmonary artery obstruction
• 5. PH with unclear mechanisms
• 3. PH due to lung diseases and/or hypoxia
• 2. PH due to left heart disease
• 1. Pulmonary Arterial Hypertension

1.1 Idiopathic PAH 1.2 PAH with long-term response to Ca blockers 1.3 Heritable PAH (Table 1) 1.4 Drugs and Toxins induced (Table 2) 1.5 Associated with; 1.4.1 Connective tissue disease (Table 3) 1.5.2 HIV infection 1.5.3 Portal hypertension 1.5.4 Congenital heart diseases (Table 4) 1..5 Schistosomiasis 1.6 PAH with overt signs of venous/capillaries ( PVOD/PCH) involvement (Table 5 & 6) 1.7 PPHN Syndrome (Table P1) 2.1 PH due to Heart Failure with preserved E.F. 2.2 PH due to Heart Failure with reduced E.F. 2.3 Valvular Disease 2.4 Congenital Post-Capillary Obstruction (Table P2) 3.1 Chronic obstructive Lung Diseases 3.2 Interstitial Lung Diseases 3.3 Other LD with restrictive/obstructive pattern 3.4 Hypoxia without lung diseases 3.5 Developmental Lung Disorders (Table P3) 4.1 Chronic Thromboembolic PH 4.2 Other Pulmonary artery obstructions (Table 7) 5.1 Haematologic disorders (Table 8) 5.2 Systemic disorders ( Table 8) 5.3 Others 5.4 Complex CHD (Table P4)

Updated clinical classification ( Nice 2018)

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Patient

• Infant 4 months of age
• Down syndrome
• cAVSD
• Feeding difficulties with recurrent aspiration
• Typical midfacial hypoplasia, obstructive

ventilation

• Recurrent respiratory tract infections

PULMONARY HYPERTENSION

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Multifactorial P(A)H?

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Coping with the Heterogeneity in Neonatal/Pediatric Pulmonary Vascular Disease

• Neonatal/Pediatric PVD is a hetereogeneous clinical disease
• To move beyond individual cases,

look for similarities, not for differences

• Clinical classification is pivotal for:
• Common language
• Collection of epidemiological data (incidence, presentation, course)
• Developing tratment strategies
• Understanding of the disease
• A perfect, flawless clinical classification will never exist
• Risk of classification: missing details (phenotyping, comorbidities)
• Optimal clinical phenotyping is crucial for understanding and interpreting

relation with genetic and biological mechanisms in order to come to precision medicine

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Precision Medicine

The focus is

• n identifying which

approaches will be effective for which patients based on genetic, environmental and lifestyle factors…

PAH PAH

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Center for Congenital Heart Disease

Beatrix Children’s Hospital UMC Groningen

Table P1. PPHN Syndrome - Associated Conditions

Idiopathic PPHN Down syndrome Meconium aspiration syndrome Respiratory distress syndrome Transient tachypnea of the newborn Pneumonia/sepsis Developmental lung disease (DLD) Perinatal stress Myocardial dysfunction (asphyxia, infection) Structural cardiac diseases: Hepatic and Cerebral arteriovenous malformations (AVMs) Associations with other diseases Placental dysfunction (PE, chorioamnionitis, maternal htn) Metabolic disease Maternal drug use or smoking

Center for Congenital Heart Disease

Beatrix Children’s Hospital UMC Groningen

Table P2. Congenital post-capillary obstructive lesions

• Pulmonary Vein Stenosis

– Isolated – Associated (Bronchopulmonary dysplasia, prematurity)

• Cor triatriatum
• Obstructed total anomalous pulmonary venous return
• Mitral/aortic stenosis (including supra/sub valvular)
• Coarctation of the aorta

Center for Congenital Heart Disease

Beatrix Children’s Hospital UMC Groningen

Table P3. Developmental Lung Disorders

• Bronchopulmonary Dysplasia
• Congenital Diaphragmatic Hernia
• Down Syndrome
• Alveolar Capillary Dysplasia with “Misalignment of Veins” (FOXF1)
• Lung Hypoplasia, Acinar Dysplasia
• Surfactant Protein Abnormalities
• SPB deficiency
• SPC deficiency
• ABCA3
• TTF-1/Nkx2
• TBX4
• Pulmonary Interstitial Glycogenosis
• Pulmonary Alveolar Proteinosis
• Pulmonary Lymphangiectasia

Center for Congenital Heart Disease

Beatrix Children’s Hospital UMC Groningen

Table P4. Complex CHD

• Segmental Pulmonary Hypertension

– Isolated pulmonary artery of ductal origin – Absent pulmonary artery – Pulmonary atresia with VSD MAPCAS – Hemitruncus – Other

• Single Ventricle

– Unoperated – Operated

• Scimitar syndrome

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Center for Congenital Heart Disease

Beatrix Children’s Hospital UMC Groningen

Table 4. Clinical Classification of PAH Associated with CHD

• A. Eisenmenger Syndrome
• B. Left to Right Shunts
• Non-correctable
• Correctable
• C. PAH with co-incidental CHD
• D. Post-operative PAH

Previous definition of PAH based on mean PAP > 25mmHg; PVR provides essential information for CHD patients Center for Congenital Heart Disease

Beatrix Children’s Hospital UMC Groningen

Recommendations

• Keep basic format of current classification system
• Sharpen pediatric disorders within this system
• expand developmental lung disorders
• keep PPHN as category
• add category related to “pulmonary vascular dysgenesis”
• addition of Down syndrome as unique class
• highlight genetic syndromes assd. with PH
• strong listing of metabolic causes of PH
• clarify non-shunt related CHD -associated PH disorders

Center for Congenital Heart Disease

Beatrix Children’s Hospital UMC Groningen

Groningen, the Netherlands